Sphingosine 1-Phosphate Receptor 1 and 5 Reciprocally Regulate IL-13 and IL-9 Production in Atopic Dermatitis

Atopic dermatitis (AD) is a common inflammatory skin disease associated with Th2, Th9, and Th22 skewing. Recent studies have implicated various lipid mediators in modulating T helper cell responses. However, the relationship between lipid mediators and Th skewing in AD is not fully understood.

We sought to identify lipid mediators that modulate cytokine production involved in Th skewing in AD.

RNA-sequencing was performed in CD3⁺ T cells and CD3- non-T cells from AD patients and healthy subjects. Differentially expressed genes were analyzed to detect candidate lipid mediators. Intracellular cytokine staining (ICS) was used to evaluate production of polarizing cytokines in CD4⁺ T cells cultured in vitro with various lipid mediators.

Several lipid mediator-related genes, including sphingosine 1-phosphate receptor 5 (S1PR5), were differentially expressed in CD3+ and CD3- cells from AD patients. ICS revealed markedly increased IL-13 and IL-9 production in the presence of S1P, with AD patients expressing higher levels of S1P in serum compared to healthy controls. Further mechanistic studies using siRNA knockdown for S1PR5 and S1PR1 revealed that IL-13 and IL-9 production are suppressed via S1PR5 and enhanced via S1PR1 signaling.

S1P signaling contributes to Th2/Th9-driven inflammation in AD by reciprocally regulating IL-13 and IL-9 production via S1PR5 and S1PR1.